Organ transplantation elicits a complex series of immunologic processes that are generally categorized as inflammation, immunity, tissue repair and structural reinforcement of damaged tissues. Macrophages and T cells mediate inflammation by the secretion of proinflammatory cytokines, e.g., interleukin-2 (IL-2), and by the activation of biochemical cascades such as the classic complement cascade. The medical community is in need of novel immunosuppressive agents [Chiu et al., 2004]. Immunosuppressive drugs fall into five groups: (i) regulators of gene expression; (ii) alkylating agents; (iii) inhibitors of de novo purine synthesis; (iv) inhibitors of de novo pyrimidine synthesis; and (v) inhibitors of kinases and phosphatases [Allison, 2000]. Glucocorticoids exert immunosuppressive and anti-inflammatory activity mainly by inhibiting the expression of the genes for IL-2 and other mediators [Ong et al., 2007]. Cyclophosphamide suppresses immune responses mediated by B-lymphocytes [Turk, 1964; Rollinghoff et al., 1977]. Methotrexate and its polyglutamate derivatives suppress inflammatory responses through release of adenosine [Turk, 1964]. Mycophenolic acid and mizoribine inhibit inosine monophosphate dehydrogenase [Allison et al., 1991; Itoh, 1993]. Mycophenolic acid induces apoptosis of activated T-lymphocytes [Dayton et al., 1992; Cohn et al., 1999]. A leflunomide metabolite and brequinar inhibit dihydroorotate dehydrogenase [Waer, 1996; Herrmann et al., 2000]. Cyclosporine and FK-506/Tacrolimus inhibit the phosphatase activity of calcineurin [Curtis, 1986; Kino et al., 1987; Liu et al., 1991; Herman, 1999; Hojo et al., 1999]. Rapamycin inhibits signal transduction from the IL-2, epidermal growth factor and other cytokine receptors [Gonzalez et al., 2001]. Immunosuppressive and anti-inflammatory compounds in development include inhibitors of p38 kinase and of the type IV isoform of cyclic AMP phosphodiesterase, which is expressed in lymphocytes and monocytes [Thomson, 1994; Abraham et al., 1996; Dodge, 1999].
Immunosuppressive medications are associated with toxicity due to their non-specific immunosuppressive effects. Reducing immunosuppression can prevent side effects related to over-immunosuppression. However, since the intrinsic immunosuppressive requirements for each donor recipient pair are unknown, immunosuppressive minimization carries a potential risk of under-immunosuppression and consequent acute rejection, premature graft loss and death. A promising future application of immunosuppressive drugs is their use in regimens designed to induce tolerance to allografts. The first step in finding such drugs is a search for agents that inhibit T cell proliferation by novel mechanisms, as the currently used agents, which all possess non-specific broad immunosuppressive effects. In our search for compounds that inhibit T cell proliferation we chose a known chemical scaffold, the quinazoline moiety, which has been utilized to develop tyrosine phosphorylation inhibitors. Quinazolines serve as the backbone for a range of inhibitors. Quinazoline-based tyrosine kinase inhibitors include: the reversible EGFR inhibitors, Gefitinib/Iressa/ZD1839 and Erlotinib/Tarceva; the dual EGFR-HER2 inhibitor, Lapatinib/Tykerb/GW572016; and the irreversible EGFR inhibitor, CI-1033 (reviewed in [Levitzki et al., 2006]). Quinazolines also form the basis for inhibitors of serine/threonine kinases, such as CDK [Brasca et al., 2009] and for a thymidylate synthase inhibitor [Jones et al., 1981; Aherne et al., 1998; Skelton et al., 1998; Theti et al., 2003].
EP 1277738A1 discloses fused heteroaryl derivatives, which are useful as medicaments, more particularly as phosphatidylinositol 3-kinase (PI3K) inhibitors and carcinostatic agents.
WO 02/076976 and WO 03/059913 teach quinazoline based compounds, their syntheses and use as Rho-kinase inhibitors. These compounds are said to be useful for inhibiting tumor growth, treating erectile dysfunction, and treating other indications mediated by Rho-kinase, e.g., coronary heart disease.
WO 03/049739 discloses pyrimidine-based compounds useful as gsk-3 inhibitors and their use in the treatment of various protein kinase mediated disorders, such as diabetes, cancer, stroke and Alzheimer's disease.
WO 03/104230 discloses bicyclic pyrimidine derivatives, said to have anti-inflammatory effect and an effect of controlling the function(s) of the Th2 cell chemoattractants TARC and/or MDC.
WO 03/097615 and U.S. Pat. No. 6,476,031B1 are directed to quinazoline derivatives and their use for inhibiting TGF-β and/or p38-α kinase.